Pharmacokinetic and pharmacodynamic studies with two α‐adrenoceptor antagonists, doxazosin and prazosin in the rabbit

Abstract

The cardiovascular effects of doxazosin, a quinazoline derivative related to prasozin were investigated and compared to prazosin in the rabbit. Radioligand binding studies using rabbit cerebral membranes showed that both doxazosin and prazosin were roughly equipotent at displacing [3H]‐prazosin from specific binding sites. However, the lower pA2 value for doxazosin at α1‐adrenoceptors in isolated thoracic aorta preparations suggests a lower potency compared to prazosin. The dose‐related pressor effects of intravenous phenylephrine were used to assess vascular α1‐adrenoceptor antagonism in vivo. There was a close agreement between α1‐adrenoceptor antagonist potency and maximum hypotensive effects with both doxazosin and prazosin. The α1‐adrenoceptor antagonist effects of doxazosin were more prolonged than those of prazosin. Studies using either radioligand binding or pressor responses to B‐HT 920 showed that doxazosin did not show any significant affinity for the α2‐adrenoceptor. Similarly, no direct vasodilator effects were observed either in animals administered angiotensin II or in isolated thoracic aorta spiral strip preparations contracted with potassium. Doxazosin has a longer terminal elimination half‐life than prazosin. The pharmacokinetics of doxazosin were linear over the dose range examined. Following pharmacological ‘autonomic blockade’ and treatment with prazosin, doxazosin did not cause any further fall in blood pressure. These observations suggest that doxazosin, like prazosin, appears to exert its hypotensive action through α1‐adrenoceptor antagonism. The prolonged fall in blood pressure and well sustained α1‐adrenoceptor antagonism after doxazosin raise the possibility of an active metabolite which also has α1‐adrenoceptor blocking properties. 1985 British Pharmacological Society